Abstract
The neonatal Fc receptor (FcRn) plays key roles in IgG and albumin homeostasis, maternal IgG transport, and antigen presentation of IgG-opsonized antigens. Previously, we reported that transgenic (Tg) mice that overexpress the bovine FcRn (bFcRn) have augmented T-dependent humoral immune response with increased IgG protection, higher level of antigen-specific antibodies, greater number of antigen-specific B cells, and effective immune response even against weakly immunogenic epitopes. In the current study, we analyzed the localization of the bFcRn in secondary lymphoid organs, and focused to demonstrate the in vivo impact of its overexpression in the spleen on the course of antibody production. bFcRn was highly expressed by red pulp macrophages and marginal zone macrophages in the spleen and by subcapsular sinus macrophages and macrophage-like cells in the interfollicular areas in the lymph node cortex. We also demonstrated that splenic dendritic cells of Tg mice express bFcRn and intraperitoneal immunization of these mice with T-dependent antigens led to more than threefold increase in the number of antigen-specific activated T helper cells with increased size and numbers of germinal centers compared to wild-type controls. bFcRn expression in splenic B cells was also detected and that may also contribute to the enhanced B cell activation. Finally, we demonstrated that these Tg mice developed efficient immune response against very low dose of antigen, reflecting another important practical benefit of these Tg mice.
Highlights
Based on a recent survey, wild-type mice are the source of two-third of all late stage and marketed therapeutic monoclonal antibodies, primarily in the form of humanized antibodies [1]
To test whether the expression of transgene containing all regulatory elements of the bovine FcRn (bFcRn) gene or its chromosomal integration influences the architecture of spleen, we compared the structure of the wt and Tg spleen using tissue immunofluorescence for lymphoid compartmentalization and the expression pattern of endogenous mouse FcRn (mFcRn) and transgenic bFcRn, respectively
We found that the spleen of Tg mice showed normal T, B cell, and marginal zone (MZ) compartmentalization indistinguishable from wt controls using Thy-1, B220, Gr1, or MadCAM-1-specific labeling (Figure 1)
Summary
Based on a recent survey, wild-type (wt) mice are the source of two-third of all late stage and marketed therapeutic monoclonal antibodies (mAbs), primarily in the form of humanized antibodies [1]. There has been an increasing demand for the development of faster and more efficient technologies for the production of high-affinity mAbs against specific epitopes of targets that are considered to be weakly immunogenic or even tolerogenic. It is important to increase the efficiency of the humoral immune response of the mouse to enhance their capability to produce hybridomas against challenging targets. The neonatal Fc receptor (FcRn) was originally identified as the protein that mediates the maternal immune transport [2, 3], it was soon realized that this receptor is a key player in regulating the transport of IgG within and across cells of diverse origins. FcRn serves to rescue IgG and albumin in capillary endothelial and hematopoietic cells from degradation, prolonging their half-lives [4]. FcRn was demonstrated to play major roles in antigen (Ag) presentation in case of Ag–IgG immune complexes (IC) by professional Ag-presenting cells (APCs) stimulating MHC class II and MHC class I-related T cell activation [5]
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